Pathological Role of Phosphoglycerate Kinase 1 in Balloon Angioplasty-Induced Neointima Formation

Abstract

Restenosis is a common vascular complication after balloon angioplasty. Catheter balloon inflation-induced transient ischemia (hypoxia) of local arterial tissues plays a pathological role in neointima formation. Phosphoglycerate kinase 1 (PGK1), an adenosine triphosphate (ATP)-generating glycolytic enzyme, has been reported to associate with cell survival and can be triggered under hypoxia. The purposes of this study were to investigate the possible role and regulation of PGK1 in vascular smooth muscle cells (VSMCs) and balloon-injured arteries under hypoxia. Neointimal hyperplasia was induced by a rat carotid artery injury model. The cellular functions and regulatory mechanisms of PGK1 in VSMCs were investigated using small interfering RNAs (siRNAs), chemical inhibitors, or anaerobic cultivation. Our data indicated that protein expression of PGK1 can be rapidly induced at a very early stage after balloon angioplasty, and the silencing PGK1-induced low cellular energy circumstance resulted in the suppressions of VSMC proliferation and migration. Moreover, the experimental results demonstrated that blockage of PDGF receptor-β (PDGFRB) or its downstream pathway, the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) axis, effectively reduced hypoxia-induced factor-1 (HIF-1α) and PGK1 expressions in VSMCs. In vivo study evidenced that PGK1 knockdown significantly reduced neointima hyperplasia. PGK1 was expressed at the early stage of neointimal formation, and suppressing PGK1 has a potential beneficial effect for preventing restenosis.

Pathogenesis and Clinical Significance of In-Stent Restenosis in Patients with Diabetes

“…The activity of phosphoglycerate kinase 1 (PGK1), a glycolytic enzyme, is associated with cell survival under hypoxia. As a result of PTA-induced arterial wall injury, PGK1 expression has been shown to increase, and the inhibition of PGK1 activity inhibits VSMCs migration and proliferation, leading to the suppression of neointima formation [101].…”

Novel Targets for Old and Diseased Hearts

“…Available drugs able to interfere with platelet aggregation are associated with increased risk of hemorrhage, warranting the development of effective, yet safer, anti-platelet drugs. The work by Barrachina et al has identified a compound, called Idelalisib, which potently inhibits platelet adhesion and aggregation by blocking Phosphoinositide 3-kinases (PI3K), but shows minimal bleeding effects in mice, compared to standard anti-platelet therapy, such as aspirin and clopidogrel, in mouse models [ 5 , 6 ].…”

“…Recurrence of arterial stenosis (restenosis) after percutaneous transluminal coronary angioplasty (PTCA) is a frequent maladaptive response, occurring in up to 50% of patients, often requiring target vessel revascularization at one year, and associated with increased morbidity, mortality and health care costs. Pan and colleagues add a piece of evidence on the pathogenesis of the disease and provide novel insight into the role of phosphoglycerate kinase 1 (PGK1) in the regulation of vascular smooth muscle cell proliferation and neointima formation in hypoxic conditions [ 6 ]. Using both primary cell cultures and a rat carotid artery injury model, they showed that PGK1 is rapidly induced early after balloon angioplasty and that its inhibition effectively reduced neointima formation, thus providing evidence that a short-term intervention targeting early response genes could be as effective in preventing restenosis as long-term drug release [ 6 ].…”